Serotonergic tone plays an important role in mental health, with dysfunction implicated in many prominent neuropsychiatric disorders including depression, schizophrenia, and addictive personality disorders. This grant investigates neurogenetic variation in the serotonin system by developing and exploiting naturally occurring homologous variation in rhesus monkeys. Our focus is on functional polymorphisms in tryptophan hydroxylase 2 (TPH2), serotonin transporter (SERT) and monoamine oxidase A (MAOA) genes in an effort to more accurately model serotonergic neurogenetic variance associated with human mental health disorders in rhesus monkeys. In Specific Aim 1, we will identify polymorphisms and haplotypes in rhesus monkey TPH2, SERT and MAOA genes, develop detection assays and genotype the NEPRC rhesus monkey colony. In Specific Aim 2, we will functionally assess rhesus monkey TPH2, SERT, and MAOA variants in vitro and compare these to human functional variants in the orthologous genes. Specific Aim 3 focuses on genotype/phenotype relationships in rhesus monkeys by assessing SERT function and SERT mRNA expression in platelets and immortalized B cell lines derived from SERT-genotyped rhesus monkeys, and by assessing cognitive phenotype in TPH2-, SERT-, and MAOA-genotyped rhesus monkeys. The research will develop rhesus monkeys as models of human neurogenetic variance related to phenotypes, behaviors and traits associated with neuropsychiatric and substance abuse disorders and clarify genetic interactions influencing distinct genotype/phenotype relationships influencing mental health. PUBLIC HEALTH RELEVANCE: Studies in this grant identify novel polymorphisms in serotonergic genes in rhesus monkeys. We will assess the function of TPH2, SERT, and MAOA polymorphisms and haplotypes derived from rhesus monkeys in vitro, and compare these to human functional variants in the orthologous genes which are implicated in mental health disorders. We will also assess the association between the identified functional variants in rhesus monkeys and measures of serotonin transporter function ex vivo and cognitive flexibility in vivo.